Circular RNAs:Diagnostic and Therapeutic Perspectives in CNS Diseases

Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and pathology.In particular,accumulating data on circRNA functions in various central nervous system(CNS)diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders.In this review,we focus on the regulatory and functional roles of circRNAs in CNS diseases,highlighting their diagnostic and therapeutic potential,with the aim of providing new insights into CNS diseases.

Engagement of N^(6)-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2

The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m^(6)A modifications.Our findings provide functional insight into the correlation between circHECW2 and m^(6)A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.

Prognostic value of time-varying dead space estimates in mechanically ventilated patients with acute respiratory distress syndrome

Background The dead space fraction(VD/VT)has proven to be a powerful predictor of higher mortality in acute respiratory distress syndrome(ARDS).However,its measurement relies on expired carbon dioxide,limiting its widespread application in clinical practice.Several estimates employing routine variables have been found to be reliable substitutes for direct measurement of VD/VT.In this study,we evaluated the prognostic value of these dead space estimates obtained in the first 7 days following the initiation of ventilation.Methods This retrospective observational study was conducted using data from the Chinese database in intensive care(CDIC).Eligible participants were adult ARDS patients receiving invasive mechanical ventilation while in the intensive care unit between 1st January 2014 and 31st March 2021.We collected data during the first 7 days of ventilation to calculate various dead space estimates,including ventilatory ratio(VR),corrected minute ventilation(V_(Ecorr)),VD/VT(Harris–Benedict),VD/VT(Siddiki estimate),and VD/VT(Penn State estimate)longitudinally.A time-dependent Cox model was used to handle these time-varying estimates.Results A total of 392 patients(median age 66[interquartile range:55–77]years,median SOFA score 9[interquartile range:7–12])were finally included in our analysis,among whom 132(33.7%)patients died within 28 days of admission.VR(hazard ratio[HR]=1.04 per 0.1 increase,95%confidence interval[CI]:1.01 to 1.06;P=0.013),V_(Ecorr)(HR=1.08 per 1 increase,95%CI:1.04 to 1.12;P<0.001),VD/VT(Harris–Benedict)(HR=1.25 per 0.1 increase,95%CI:1.06 to 1.47;P=0.006),and VD/VT(Penn State estimate)(HR=1.22 per 0.1 increase,95%CI:1.04 to 1.44;P=0.017)remained significant after adjustment,while VD/VT(Siddiki estimate)(HR=1.10 per 0.1 increase,95%CI:1.00 to 1.20;P=0.058)did not.Given a large number of negative values,VD/VT(Siddiki estimate)and VD/VT(Penn State estimate)were not recommended as reliable substitutes.Long-term exposure to VR>1.3,V_(Ecorr)>7.53,and VD/VT(Harris–Benedict)>0.59 was independently associated with an increased risk of mortality in ARDS patients.These findings were validated in the fluid and catheter treatment trial(FACTT)database.Conclusions In cases where VD/VT cannot be measured directly,early time-varying estimates of VD/VT such as VR,,V_(Ecorr),and VD/VT(Harris–Benedict)can be considered for predicting mortality in ARDS patients,offering a rapid bedside application.

Malnutrition predicts poor outcomes in diabetic COVID-19 patients in Huangshi,Hubei

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has spread throughout the world,which becomes a global public health emergency.Undernourishment prolongs its convalescence and has an adverse effect on its prognosis,especially in diabetic patients.The purpose of this study was to evaluate the prevalence and characteristics of undernourishment and to determine how it is related to the prognostic outcomes in the diabetic patients with coronavirus disease 2019(COVID-19).A retrospective,multicenter study was conducted in 85 diabetic COVID-19 patients from three hospitals in Hubei Province.All patients were assessed using the European Nutritional Risk Screening 2002(NRS-2002)and other nutritional assessments when admitted.Of them,35(41.18%)were at risk of malnutrition(NRS score≥3).Severe COVID-19 patients had a significantly lower level of serum albumin and prealbumin and higher NRS score than non-severe patients.Multivariate logistic regression analysis showed that serum prealbumin and NRS score increased the likelihood of progression into severe status(P<0.05).Meanwhile,single factor and multivariate analysis determined that grade of illness severity was an independent predictor for malnutrition.Furthermore,prealbumin and NRS score could well predict severe status for COVID-19 patients.The malnutrition group(NRS score≥3)had more severe illness than the normal nutritional(NRS score<3)group(P<0.001),and had a longer length of in-hospital stay and higher mortality.Malnutrition is highly prevalent among COVID-19 patients with diabetes.It is associated with severely ill status and poor prognosis.Evaluation of nutritional status should be strengthened,especially the indicators of NRS-2002 and the level of serum prealbumin.

Aerosol therapy during mechanical ventilation in intensive care units: A questionnaire-based survey of 2203 ICU medical staffin China

Background:To describe the current status of aerosol therapy during mechanical ventilation(MV)and the prac-tice,knowledge,and beliefs about aerosol therapy in physicians working in the intensive care unit(ICU)in China.Methods:A physician self-administered questionnaire-based cross-sectional survey was carried out from January 2019 to July 2019.An electronic questionnaire was designed,and physicians who worked regularly in ICUs across several hospitals were contacted through WeChat.Answers to all questions and the general characteristics of physicians who answered the questionnaire were collected and analyzed.Results:A total of 2203 medical staffwho regularly worked in the ICUs completed this questionnaire(9.0%missing data);87.7%of the participants were doctors.Most respondents claimed that they often administered aerosolization therapy.Ultrasonic atomizer(50.7%)and jet nebulizer(48.6%)were the most commonly used atomization devices.Bronchodilators(65.8%)and steroids(66.3%)were the most frequently aerosolized drugs during MV.During nebulization,ventilator settings were never changed by 32.7%of respondents.Only 49.1%of respondents knew the appropriate place for a nebulizer.Further,62.7%of respondents using heated humidifiers reported turning them offduring nebulization.Specific knowledge about droplet size and nebulization yield was poor.Respondents from tertiary hospitals and those with higher technical title or work experience tended to have better accuracy than those from primary hospitals or with lower technical titles(P<0.050).Conclusions:Aerosol therapy was commonly used during MV,and the most frequent drugs were bronchodila-tors and steroids.Scientific knowledge about the optimal implementation of aerosol therapy during MV seemed deficient.

Expert consensus on the diagnosis and treatment of severe and critical coronavirus disease 2019(COVID-19)

Introduction Coronavirus disease 2019(COVID-19),a disease caused by severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2),is highly contagious[1]and has developed into a global pan-demic.Up to July 1,2022,COVID-19 has affected>200 coun-tries and regions across the globe and caused 545,226,550 con-firmed cases and 6334,728 deaths,[2]seriously compromising human life,public properties.

An expanded definition of acute respiratory distress syndrome:Challenging the status quo

Acute respiratory distress syndrome(ARDS)is a severe form of acute hypoxic respiratory failure caused by non-cardiogenic pulmonary edema.li since it was first described 50 years ago,the definition of ARDS has been revised several times to match the needs of patients,clinicians,and investigators.

Expert consensus on blood pressure management in critically ill patients

Introduction For critically ill patients with unstable hemodynamics,goal‑directed therapy for arterial blood pressure is needed with continuous daily bedside monitoring.The prevalence of hypertension in Chinese adults is 25.2%,of which 1–2%of patients may experience a hypertensive emergency,with a mortality rate of 6.9%in the acute phase.The mortality and readmission rates within 90 days of onset are as high as 11%.[1]Furthermore,the mortality rate for patients who experience hypertensive emergencies can reach 50%within 12 months of the incident.[2]The incidence of perioperative hypertension in patients undergoing cardiac surgery is approximately 50%,with this figure dropping to 25%for non-cardiac surgery.Surgery may increase the incidence of perioperative cardio-cerebrovascular adverse events by 3–5%.[3]

Coupling WO_(3-x) dots-encapsulated metal-organic frameworks and template-free branched polymerization for dual signal-amplified electrochemiluminescence biosensing

Developing accurate and sensitive DNA methyltransferase(MTase) analysis methods is essential for early clinical diagnosis and development of antimicrobial drug targets. In this work, by coupling WO_(3-x) dotsencapsulated metal-organic frameworks(MOFs) as co-reactants and terminal deoxynucleotidyl transferase(Td T)-mediated template-free branched polymerization, a dual signal-amplified electrochemiluminescent(ECL) biosensor was constructed to detect DNA adenine methylation(Dam) MTase. The employment of WO_(3-x) dots-encapsulated MOFs(i.e., NH_(2)-UIO66@WO_(3-x) ) was not only beneficial for biomolecule conjugation because of the abundant amino groups but also led to a 7-fold enhanced ECL response due to the increased loading of WO_(3-x). Moreover, Td T-mediated template-free branched polymerization promoted the capture of ECL emitters on the electrode surface, achieving 20-fold enhanced signal amplification. The presented ECL biosensor demonstrated a low detection limit of 2.4 × 10^(-4)U/m L, and displayed high reliability for the detection of Dam MTase in both spiked human serum and E. coli cell samples, and for the screening of potential inhibitors. This study opens a new avenue for designing a dual signal amplificationbased ECL bioassay for Dam MTase and screening inhibitors in the fields of clinical diagnosis and drug development.

Neural control of pressure support ventilation improved patient-ventilator synchrony in patients with different respiratory system mechanical properties:a prospective,crossover trial

Background:Conventional pressure support ventilation(PSP)is triggered and cycled off by pneumatic signals such as flow.Patient-ventilator asynchrony is common during pressure support ventilation,thereby contributing to an increased inspiratory effort.Using diaphragm electrical activity,neurally controlled pressure support(PSN)could hypothetically eliminate the asynchrony and reduce inspiratory effort.The purpose of this study was to compare the differences between PSN and PSP in terms of patient-ventilator synchrony,inspiratory effort,and breathing pattern.Methods:Eight post-operative patients without respiratory system comorbidity,eight patients with acute respiratory distress syndrome(ARDS)and obvious restrictive acute respiratory failure(ARF),and eight patients with chronic obstructive pulmonary disease(COPD)and mixed restrictive and obstructive ARF were enrolled.Patient-ventilator interactions were analyzed with macro asynchronies(ineffective,double,and auto triggering),micro asynchronies(inspiratory trigger delay,premature,and late cycling),and the total asynchrony index(AI).Inspiratory efforts for triggering and total inspiration were analyzed.Results:Total AI of PSN was consistently lower than that of PSP in COPD(3%vs.93%,P=0.012 for 100%support level;8%vs.104%,P=0.012 for 150%support level),ARDS(8%vs.29%,P=0.012 for 100%support level;16%vs.41%,P=0.017 for 150%support level),and post-operative patients(21%vs.35%,P=0.012 for 100%support level;15%vs.50%,P=0.017 for 150%support level).Improved support levels from 100%to 150%statistically increased total AI during PSP but not during PSN in patients with COPD or ARDS.Patients’inspiratory efforts for triggering and total inspiration were significantly lower during PSN than during PSP in patients with COPD or ARDS under both support levels(P<0.05).There was no difference in breathing patterns between PSN and PSP.Conclusions:PSN improves patient-ventilator synchrony and generates a respiratory pattern similar to PSP independently of any level of support in patients with different respiratory system mechanical properties.PSN,which reduces the trigger and total patient’s inspiratory effort in patients with COPD or ARDS,might be an alternative mode for PSP.Trial Registration:ClinicalTrials.gov,NCT01979627;https://clinicaltrials.gov/ct2/show/record/NCT01979627.

Adsorptive hemofiltration for sepsis management: expert recommendations based on the Asia Pacific experience

To the Editor:In sepsis,bacterial endotoxins play a central role by inducing a dysregulated and exaggerated release of inflammatory mediators and cytokines,often described as the“cytokine storm”or“cytokinemia.”[1]Both endotoxins and cytokines have been implicated in the development of organ dysfunction,including acute kidney injury(AKI).[2]Removing circulating endotoxins and excess cytokines from the circulation restores chemotactic gradients,localizing the immune response to the principal site of infection and re-establishing a regulated immune response.[1,3]Therefore,using hemofilters with enhanced endotoxin and cytokine adsorptive properties may bring about additional therapeutic benefits compared with conventional continuous renal replacement therapy(CRRT)filters.

Super-sensitive bifunctional nanoprobe: Self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment;however,biocompatibility and targeted penetration of these nanomaterials remain as limitations,which lead to serious side effects and significantly narrow the scope of their application.The self-assembly of intermediate filaments with arginine-glycine-aspartate(RGD)peptide(RGDIFP)was triggered by the hydrophobic cationic molecule 7-amino actinomycin D(7-AAD)to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor treatment.The designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method.This fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes,ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted DNA.It is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential,but also potent antitumor therapeutic effects in vivo.The proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

Clinical characteristics of patients with COVID-19 in Huangshi, China

Dear Editor,The first coronavirus disease 2019(COVID-19)outbreak was reported in Wuhan,Hubei,China.As one of the cities closest to Wuhan,Huangshi is considered a subcenter of the Wuhan metropolitan area.This study was carried out to describe the characteristics of adult patients with confirmed COVID-19 in Huangshi.

Hepatocyte growth factor protects pulmonary endothelial barrier against oxidative stress and mitochondria-dependent apoptosis

Background:Pulmonary microvascular endothelial cells(PMVECs)were not complex,and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury(ALI)/acute respiratory distress syndrome(ARDS).Previous studies have demonstrated that hepatocyte growth factor(HGF),which was secreted by bone marrow mesenchymal stem cells,could decrease endothelial apoptosis.We investigated whether mTOR/STAT3 signaling acted in HGF protective effects against oxidative stress and mitochondria-dependent apoptosis in lipopolysaccharide(LPS)-induced endothelial barrier dysfunction and ALI mice.Methods:In our current study,we introduced LPS-induced PMEVCs with HGF treatment.To investigate the effects of mammalian target of rapamycin(mTOR)/signal transducer and activator of transcription 3(STAT3)pathway in endothelial oxidative stress and mitochondria-dependent apoptosis,mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 were,respectively,used to inhibit mTOR/STAT3 signaling.Moreover,lentivirus vector-mediatedmTORC1(Raptor)andmTORC2(Rictor)gene knockdown modifications were introduced to evaluatemTORC1 andmTORC1 pathways.Calcium measurement,reactive oxygen species(ROS)production,mitochondrial membrane potential and protein,cell proliferation,apoptosis,and endothelial junction protein were detected to evaluate HGF effects.Moreover,we used the ALI mouse model to observe the mitochondria pathological changes with an electron microscopein vivo.Results:Our study demonstrated that HGF protected the endothelium via the suppression of ROS production and intracellular calcium uptake,which lead to increased mitochondrial membrane potential(JC-1 and mitochondria tracker green detection)and specific proteins(complex I),raised anti-apoptosis Messenger Ribonucleic Acid level(B-cell lymphoma 2 and Bcl-xL),and increased endothelial junction proteins(VE-cadherin and occludin).Reversely,mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 could raise oxidative stress and mitochondria-dependent apoptosis even with HGF treatment in LPS-induced endothelial cells.Similarly,mTORC1 as well as mTORC2 have the same protective effects in mitochondria damage and apoptosis.Inin vivo experiments of ALI mouse,HGF also increased mitochondria structural integrity via the mTOR/STAT3 pathway.Conclusion:In all,these reveal that mTOR/STAT3 signaling mediates the HGF suppression effects to oxidative level,mitochondria-dependent apoptosis,and endothelial junction protein in ARDS,contributing to the pulmonary endothelial survival and barrier integrity.

It is time to update the ARDS definition: It starts with COVID-19-induced respiratory failure

Coronavirus disease 2019(COVID-19)may rapidly worsen respiratory failure,thereby leading to death.COVID-19-induced respiratory failure exhibits some atypical characteristics,silent hypoxemia,and high lung compliance.Some histopathological changes associated with COVID-19-induced respiratory failure differ from those of classic acute respiratory distress syndrome(ARDS).However,compared with classical ARDS,COVID-19-induced respi-ratory failure has a similar timing of onset,clinical syndromes,radiological profile,and mortality rate in the intensive care unit(ICU).Respiratory failure induced by COVID-19 is a type of ARDS and is currently underdiag-nosed.This condition stretches the definition of classic ARDS;therefore,an updated definition is warranted.

LncRNA HCP5-encoded protein contributes to adriamycin resistance through ERK/mTOR pathway-mediated autophagy in breast cancer cells

Adriamycin(ADR),also known as doxorubicin,is an anthracycline anticancer drug and a chemotherapeutic drug commonly used in breast cancer treatments.1 However,breast cancer patients can gradually become tolerant to chemotherapy.Therefore,improving the curative effect of ADR remains an urgent problem to be solved.Autophagy is a complex catabolic process;normal living cells break down damaged organelles or aggregated molecules and absorb energy to maintain homeostasis through autophagy.